The present invention relates to a method of preparing a freeze-dried (or "lyophilized") formulation containing a drug or a mixture of drugs, which enables the freeze-drying technique to be used even in many cases where freeze-drying has hitherto not been practical, for example in the case of drugs which can be freeze-dried only with difficulty in a single solution, or whose stability is reduced when two or more components are mixed in a single solution.
Preparation of dried formulations by freeze-drying has been widely used for a variety of pharmaceutical preparations, and much research has been carried out in an attempt to determine how various problems associated with the technique may be overcome. A general review of the freeze-drying techniques used for pharmaceuticals may be found in "The Lyophilization of Pharmaceuticals: A Literature Review" by N.A. Williams and G.P. Polli, J. Parenteral Science and Technology, 38, 48-55 (1976), the disclosure of which is incorporated herein by reference. Other specific techniques or processes for freeze-drying specific drugs are disclosed in Japanese Patent Application Kokai No. 68412/1986, J. Parenteral Science and Technology, 42, 47-52 (1988) and European Patent Application No. 211 257, the disclosures of which are incorporated herein by reference.
In essence, freeze-drying consists of at least two steps:
1. Freezing a solution or suspension (almost invariably aqueous) of the material to be freeze-dried; and
2. Raising the temperature of the frozen material so that the frozen solvent (almost invariably ice) sublimes without melting.
Freeze-dried formulations are often mixtures of two or more active ingredients, and various other components, such as vehicles, stabilizers, isotonic agents, etc., other than the active ingredients, may be added in many cases. However, the eutectic temperature of the system during freezing changes with the nature of the additives, and, in particular, the addition of an inorganic substance will often markedly lower the eutectic point [Arimoto et al, "Journal of The Research Society of Freezing and Drying", 22, 48-55 (1976)]. Also, if the aqueous solution of a principal drug has a low eutectic point, further lowering of the eutectic point may sometimes occur as a result of the inclusion of additives [Arimoto et al, "Journal of The Research Society of Freezing and Drying", 22, 48-55 (1976)].
In general, a freeze-dried composition can be prepared by freeze-drying the frozen composition at a product temperature not higher than the eutectic point, and this will give a freeze-dried product having a good appearance (N. A. Williams et al, op. cit.), but the appearance of the freeze-dried product becomes less desirable, and it may even appear syrupy, if the freeze-drying is carried out at a temperature higher than the eutectic point [Koji Ito et al. Farumashia, 5, 99 (1969)], which markedly impairs its commercial value. In practice, however, in order to increase the freeze-drying speed, it is desirable that the drying shelf temperature (and hence the product temperature) should be set at as high a temperature as possible. However, when the solution to be dried contains several different kinds of solute components, because this lowers the eutectic point, it is not easy to increase the drying temperature by very much. Accordingly, freeze-drying of a drug having a low eutectic point has to be carried out at a low temperature, but this means that the primary drying process must be effected for a long time, which adversely affects the economics of the freeze-drying process.
Various contrivances have been proposed in order to increase the speed of freeze-drying. For example, the drying speed may be considerably increased by increasing the size of the frozen ice crystals by performing a certain specific thermal treatment during freezing [see, for example, Japanese Patent Application Kokai No. 68412/1986, and J. Parenteral Science and Technology, 42, 47-52 (1988)]. Another way of increasing the speed of freeze-drying is to increase the surface area available for evaporation of moisture. In the case of a drug, where the freeze-drying normally takes place in the vial in which the drug is to be sold (for improved sterility), this may be achieved by freezing over the wall surface of the vial, with the vial containing the liquid to be freeze-dried being kept horizontal to increase the surface area and by using any of several techniques, for example: by using an automatic shell-freezer model (Virtis); by freezing to the wall surface of the vial, whilst subjecting it to high speed rotation, e.g. using a centrifugal freeze dryer model EF6 (Edwards); or by freezing and drying to form granules by adding the aqueous solution to be freeze-dried dropwise to a very cold refrigerant fluid (e.g., a fluorocarbon) or to liquid nitrogen, e.g., as described in Japanese Patent Application Kokai No. 29513/1987.
However, although low temperature drying may be achieved by the methods described above, the appearance of the dried product is frequently less than desirable or a partially syrupy dried product may be obtained. The product referred to herein as "syrupy" is a product in which a small amount of water remains, so that some part of it may resemble a syrup or a gum.
Another problem often encountered in freeze-drying is that some drugs are unstable at pH values in the region where they may be administered to the living body, but are stable in acidic or alkaline solutions. These drugs have to be formed into pharmaceutical preparations, whilst in the acidic or alkaline state, and must then be restored to around neutrality at the point of administration. For this reason, a freeze-dried preparation of this kind which, when dissolved, would have a pH outside the range that could safely or comfortably be administered to the human body is often provided to the ultimate user in association with an aqueous solution containing the necessary amount of an alkali or an acid, respectively, in order to achieve a suitable pH value. Examples of such preparations include: a preparation in which a sodium monohydrogenphosphate solution is provided in association with ademethionine (see Example 2, hereafter); and a preparation in which a sodium monohydrogenphosphate solution is provided in association with a carboquone freeze-dried product. This provision of a solution of a compensatory acid or alkali also has disadvantages of production cost, and expansion of the volume of the total preparation leads to an increase in the necessary storage space, which is undesirable to both distributors and users of pharmaceuticals.
The only method known in the prior art to overcome this drawback was to avoid the freeze-drying method and to divide the drug and the neutralizing agent in the form of powders, as such into small portions which are then placed in the vials or other vessels. However, such a powdery divided preparation has many disadvantages as compared with a freeze-dried preparation. For example: (1) it is difficult to measure small amounts accurately and reproducibly; (2) contamination may occur; (3) stability may be reduced due to the increase in the area of contact between the different components, because they were mixed in the powdery state; and (4) it is very difficult to divide strongly hygroscopic powders.
It can be seen from the above discussion that it is desirable to shorten the drying time of freeze-dried preparations, in order to reduce the production cost, in order to give a high quality preparation, and in order to improve the appearance of the freeze-dried product.
Also, for drugs which become unstable through interaction with one or more other components of the formulation, the technique used at present depends on divided preparations, but, in view of the problems of powdery divided preparations, freeze-dried preparations are preferred.
In particular in the case of the mass production of pharmaceuticals, for which sterile operation is required, these problems must be overcome.